The AIDS epidemic is one of the most challenging problems in medicine in the 21st century (United Nations. 2004 Report on the global HIV/AIDS Epidemic: 4th global report. New York, U.S.A., 2004). The disclosure of the foregoing is incorporated herein in its entirety by reference. In addition, the entirety of the disclosures of each of the publications cited herein are also incorporated herein by reference. Among many strategies to combat this disease, highly active antiretroviral therapy (HAART) with HIV protease inhibitors (PIs) in combination with reverse transcriptase inhibitors (RTIs) continues to be the first line treatment for control of HIV infection (Sepkowitz, K. A. AIDS—the first 20 years. N. Engl. J. Med. 2001, 344, 1764-1772). This treatment regimen has definitely improved quality of life, enhanced HIV management, and halted the progression of the disease. However, despite these impressive successes, there remain many challenges to treating this devastating disease, including decreasing both the toxicity and complexity of these treatment regimens. In addition, there is a growing population of patients that is developing multi-drug resistant strains of HIV, and there is ample evidence that these strains can be further transmitted (Staszewski et al., Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. N. Engl. J. Med. 1999, 341, 1865-1873; Wainberg et al., Public health implications of antiretroviral therapy and HIV drug resistance. J. Am. Med. Assoc. 1998, 279, 1977-1983).
HAART has had a major impact on the AIDS epidemic in industrially advanced nations; however, eradication of human immunodeficiency virus type 1 (HIV 1) appears to be currently unachieved, in part due to the viral reservoirs remaining in blood and infected tissues. The limitation of antiviral therapy of AIDS is also exacerbated by complicated regimens, the development of drug-resistant HIV-1 variants, and a number of inherent adverse effects.
A number of challenges have nonetheless been encountered in bringing about the optimal benefits of the currently available therapeutics of AIDS and HIV-1 infection to individuals receiving HAART (De Clercq 2002. Strategies in the design of antiviral drugs. Nat Rev Drug Discov 1:13-25; Siliciano et al. 2004. A long-term latent reservoir for HIV-1: discovery and clinical implications. J Antimicrob Chemother 54:6-9; Simon, et al. 2003. HIV-1 dynamics in vivo: implications for therapy. Nat Rev Microbiol 1:181-90). They include (i) drug-related toxicities; (ii) partial restoration of immunologic functions once individuals developed AIDS; (iii) development of various cancers as a consequence of survival prolongation; (iv) flame-up of inflammation in individuals receiving HAART or immune re-construction syndrome (IRS); and (v) increased cost of antiviral therapy. Such limitations of HAART are exacerbated by the development of drug-resistant HIV-1 variants (Carr 2003. Toxicity of antiretroviral therapy and implications for drug development. Nat Rev Drug Discov 2:624-34; Fumero et al. 2003. New patterns of HIV-1 resistance during HAART. Clin Microbiol Infect 9:1077-84; Grabar et al. 2006. HIV infection in older patients in the HAART era. J Antimicrob Chemother 57:4-7; Hirsch et al. 2004. Immune reconstitution in HIV-infected patients. Clin Infect Dis 38:1159-66; Little et al. 2002. Antiretroviral-drug resistance among patients recently infected with HIV. N Engl J Med 347:385-94).
Successful antiviral drugs, in theory, exert their virus-specific effects by interacting with viral receptors, virally encoded enzymes, viral structural components, viral genes, or their transcripts without disturbing cellular metabolism or function. However, at present, no antiretroviral drugs or agents are likely to be completely specific for HIV-1 or to be devoid of toxicity or side effects in the therapy of AIDS, which has been an issue because patients with AIDS and its related diseases will have to receive antiretroviral therapy for a long period of time, perhaps for the rest of their lives.
In one embodiment, described herein are novel non-peptidyl compounds and compositions for treating patients in need of relief from HIV, AIDS, and AIDS-related diseases. Also described herein are methods for treating such diseases. In one embodiment, it has been discovered that the non-peptidyl compounds described herein are potent inhibitors of HIV-1 protease. It has also been discovered that these compounds may offer therapeutic benefits to patients suffering from or in need of relief from HIV-1/AIDS.
In another embodiment, described herein is structure-based design of novel HIV-1 protease inhibitors (PI) incorporating a stereochemically defined 4-hexahydro-furopyranol-derived urethanes as the P2-ligand. In one aspect, the inhibitors herein are designed to make extensive interactions including hydrogen bonding with the protein backbone of the HIV-1 protease active site. In another embodiment, the inhibitors described herein appear to show excellent enzyme inhibitory activity and antiviral potency. In one aspect, this antiviral potency may be comparable to that of approved protease inhibitors. In another embodiment, the inhibitors described herein appear to show excellent activity against multi-PI-resistant variants.
In another embodiment, described herein is structure-based design of novel HIV-1 protease inhibitors (PI) incorporating hydrogen bonding residues as the P1 ligand. In one aspect, the inhibitors herein are designed to make extensive interactions including hydrogen bonding with the protein backbone of the HIV-1 protease active site. In another embodiment, the inhibitors described herein appear to show excellent enzyme inhibitory activity and antiviral potency. In one aspect, this antiviral potency may be comparable to that of approved protease inhibitors. In another embodiment, the inhibitors described herein may show excellent activity against multi-PI-resistant variants.
In one illustrative embodiment of the invention, there is provided a compound of the formula (I)
or a pharmaceutically acceptable salt thereof, wherein
A is cycloheteroalkyl or cycloheteroalkyl-alkyl, each of which is optionally substituted;
Q is oxygen, sulfur, nitrogen, or C(RaRb) where each of Ra and Rb is independently selected in each instance from the group consisting of hydrogen, alkyl, and alkoxy;
W is oxygen or sulfur;
R1 is hydrogen, a nitrogen protecting group, or a pro-drug substituent;
X is C(RaRb)n, where n is 1, 2, or 3, and each of Ra and Rb is defined as above;
R2 is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; or
R2 is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is substituted, where at least one substituent is a hydrogen bond forming group;
R3 is hydrogen, an oxygen protecting group, a phosphate derivative, or a pro-drug substituent;
R4 is alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;
Z is C(O), S(O)2, NH, NHC(O), NHS(O)2, C(O)—O, or C(O)—NR6;
R5 is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; and
R6 is hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; and wherein
the compound of formula (I) is other than one in which, together: Q is oxygen, W is oxygen, R1 is hydrogen, X is methylene, R2 is unsubstituted phenyl, R3 is hydrogen or a phosphate derivative, R4 is isobutyl, Z is S(O)2, and R5 is 4-aminophenyl or 4-methoxyphenyl when:
A is a group of the formula
wherein (*) indicates the point of attachment; in which RQ is hydrogen, hydroxy, methoxy or benzyloxy; or
A is a group of the formula
wherein (*) indicates the point of attachment; in which one of Y1 and Y2 is methylene, and the other of Y1 and Y2 is C(ReRf) or oxygen; or
A is a group of the formula
wherein (*) indicates the point of attachment;
p is 1 or 2;
Y3 and Y4 are in each instance independently methylene or oxygen;
Y5 and Y6 are in each instance independently selected from the group consisting of oxygen and alkylene, providing that at least one of Y3 and Y4 is oxygen, and wherein when one of Y3 and Y4 is optionally substituted methylene, at least one of Y5 and Y6 is oxygen, and A does not include a peroxide bond;
Y7 is a bond; and R1 of the group is hydrogen.
Certain embodiments of a compound of a formula (I) are denoted herein as a compound of formula (I1) or a compound of formula (I2). Throughout this specification (*) indicates the point of attachment for a particular radical.
In one illustrative embodiment of the invention, compounds of formula (I1)
and pharmaceutically acceptable salts thereof are described herein, wherein
A is cycloheteroalkyl or cycloheteroalkyl-alkyl, each of which is optionally substituted;
Q is oxygen, sulfur, nitrogen, or C(RaRb) where each of Ra and Rb is independently selected in each instance from the group consisting of hydrogen, alkyl, and alkoxy;
W is oxygen or sulfur;
R1 is hydrogen, a nitrogen protecting group, or a pro-drug substituent;
X is C(RaRb)n, where n is 1, 2, or 3, and each of Ra and Rb is defined as above;
R2 is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is substituted, where at least one substituent is a hydrogen bond forming group;
R3 is hydrogen, an oxygen protecting group, or a pro-drug substituent;
R4 is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;
Z is C(O), S(O)2, NH, NHC(O), or NHS(O)2; and
R5 is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted.
In one illustrative embodiment, the HIV-1 protease inhibitors described herein are compounds of the following formula (I2):
and pharmaceutically acceptable salts thereof, wherein
A is the following group, wherein (*) denotes the point of attachment:

one of Y1 and Y2 is methylene, and the other of Y1 and Y2 is defined as follows:
Y1 is C(RaRb) or oxygen; Y2 is C(RaRb), CHNRa, oxygen, or SO2, where Ra and Rb are independently selected in each instance from hydrogen, alkyl, and alkoxy; m is an integer selected from 0, 1, 2, or 3; and Rc and Rd each represent one or more optional substituents, each of which is independently selected in each instance from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkylalkoxy, aryl, arylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heteroaryloxy, and heteroarylalkoxy, each of which is itself optionally substituted;
Q is oxygen, sulfur, nitrogen, or C(RaRb); where each of Ra and Rb is independently selected in each instance from the group consisting of hydrogen, alkyl, and alkoxy;
W is oxygen or sulfur;
R1 is hydrogen, a nitrogen protecting group, or a pro-drug substituent;
X is C(RaRb)n, where each of Ra and Rb is independently selected in each instance from the group consisting of hydrogen, alkyl, and alkoxy;
R2 is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;
R3 is hydrogen, an oxygen protecting group, or a pro-drug substituent;
R4 is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;
Z is C(O), S(O)2, NH, NHC(O), or NHS(O)2; and
R5 is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;
providing that the compound of formula (I2) is not of the formula

or a pharmaceutically acceptable salt thereof.
In another embodiment, compositions containing one or more of the compounds are also described herein. In one aspect, the compositions include a therapeutically effective amount of the one or more compounds for treating a patient with HIV-1/AIDS. In another embodiment, methods for using the compounds and compositions for treating patients with HIV-1/AIDS are also described herein. In one aspect, the methods include the step of administering one or more of the compounds and/or compositions containing them to a patient with HIV-1/AIDS. In another aspect, the methods include administering a therapeutically effective amount of the one or more compounds and/or compositions described herein for treating patients with HIV-1/AIDS. Another embodiment is the use of the one or more compounds and/or compositions described herein for treating patients with HIV-1/AIDS. In another embodiment, uses of the compounds and compositions in the manufacture of a medicament for treating patients with HIV-1/AIDS are also described herein. In one aspect, the medicaments include a therapeutically effective amount of the one or more compounds and/or compositions for treating a patient with HIV-1/AIDS.
It is appreciated herein that the compounds described herein may be used alone or in combination with other compounds useful for treating HIV/AIDS, including those compounds that may operate by the same or different modes of action. In addition, it is appreciated herein that the compounds described herein may be used in combination with other compounds that are administered to treat other symptoms of HIV/AIDS.